tbuckley/cabot-search huggingface dataset:
PB1755: CLINICAL FEATURES AND BIOLOGICAL CHARACTERIZATION OF ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA TREATED IN A REGIONAL HOSPITAL IN FRANCE
Authors: Pilar Dutari, Tantrantan Leonce Adjoumani, Safia Chebrek, Thierry Takam, Hacene Zerazhi, Jesica Elizabe Weber Vidoret, Borhane Slama
Journal: HemaSphere (2023)

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: Acute lymphoblastic leukemia (ALL) is a frequent neoplasm in the pediatric population, but less frequent in adults and therefore there is less real-life bibliography published about them. Knowing the epidemiological, clinical and biological characteristics of the local population allows us to improve management and provide key data that will serve as a starting point for future research. Aims: Characterize the epidemiology, clinical presentation and cytogenetics features of the adult population diagnosed with ALL treated at the Avignon Hospital Center in France. Methods: Retrospective, descriptive, observational trial that included adults (≥ 18 years old) patients with a new diagnosis of ALL between January 2018 to December 2022 treated at the regional hospital in the south of France. Results: During the period analyzed, 29 patients with a diagnosis of ALL were treated at the Avignon’s regional hospital. The 57% were males and the median ages were 60 years old (range 22 to 87 years). Regarding the clinical manifestations at diagnosis, 28% reported B symptoms and 21% showed symptomatic adenopathies. 34% showed a platelet count of less than 30,000/mm3 and 10% of the patients presented clinical manifestations of hemorrhage. 28% had grade III-IV anemia (Hb≤7.9 G/dL). 3 patients had hyperleukocytosis (WBC > 100.000/mm3) two of which were ALL in the context of a CML evolved to blastic phase. 3 out of 26 evaluated patients had central nervous system involvement. Immunophenotypic characterization showed that B-lineage was more frequent than T-lineage ALL (70% vs 23%) and there were 2 patients with biphenotypic expression (one with myeloid/lymphoid markers and other with T/B lymphoid differentiation). In the initial cytogenetic evaluation, 6 out of 27 karyotypes were normal. 67% of the patients had cytogenetic alterations associated with unfavorable prognosis. The most frequent cytogenetic alterations found were: isolated Philadelphia Chromosome (6 patients), t(9,22) associated with other cytogenetic alterations (5 patients), complex karyotypes (3 patients). In this cohort, 24 patients (48%) presented the fusion gen BCR-ABL, 5 of which were evolution to the blast phase of a previous CML. This patients were older than those (Median age 66 vs 54 years old, p= 0.05) Summary/Conclusion: The population assisted at this regional hospital has a higher average age and therefore has a higher incidence of Philadelphia-positive ALL compared to the literature published in other regions. This study provides the basis for future longitudinal studies to analyze the evolution and survival of ALL in the region. Keywords: Acute lymphoblastic leukemia, Epidemiology
PB2414: TOTAL BODY IRRADIATION VERSUS NON TOTAL BODY IRRADIATION CONTAINING REGIMENS FOR PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Sabrine Mekni, Rimmel Yosra Kanoun, Nour Abdeljelil, Lamia Torjemane, Insaf Ben Yaiche, Dorra Belloumi, Rihab Ouerghi, Ines Turki, Saloua Ladeb, Tarek Ben Othman
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Total body irradiation (TBI) was the most common conditionning regimen used in pediatric allogeneic stem cell transplantation (ASCT) for acute lymphoblastic leukemia(ALL). Although it has shown better outcomes in this population compared to chemotherapy, its toxicity still a major issue. Aims: Our objective is to compare the efficacy and toxicity of TBI –based regimen to chemotherapy -based regimen in pediatric ASCT for ALL. Methods: Retrospective observational study conducted on patients <18 years, with ALL who underwent a first ASCT from an HLA-identical sibling donors,between February 2007 and September 2021. The pre-transplant conditioning includes TBI -based regimen (9.9 Gy given in 3 fractions over 3 days) with etoposide 60mg/kg/d for one day or chemotherapy –based regimen (busulfan,endoxan,Thiotepa,Fludarabine). Results: Seventy one patients were enrolled.The median age was 10 years (4-17) with a sex ratio (M/F)=2. Thirty eight (53.5%) had B-ALL and 33 (46.5%) had T-ALL. Forty eight (68%) patients were transplanted in first complete remission,17(24%) were in second complete remission and only 18 (25%) had a negative measurable residual disease (<10-4) in pre ASCT. The graft source was bone marrow in 61 (86%) patients and peripheral blood stem cell in 10 patients (14%). Forty eight (68%) received TBI-based regimen and 23 (32%) received chemotherapy based –regimen. The cumulative incidence (CI) of relapse was significantly lower in the TBI group (27.3% versus 53.6%; p=0.04). Cumulatives Incidences of acute and chronic graft versus host disease were similar for both groups (TBI versus chemotherapy) (37.5% versus 39.5%,p=0.18 and 21.7% versus 31.8%,p=0.35,respectively). The occurence of documented infections was 50% in the TBI group and 43.5% in the other group (p=0.6).The median time to neutrophil recovery was 27 days and 25 days, respectively (p=0.9). Consequently, the cumulative incidence of non relapse mortality did not differ between the two groups (12 % versus 9 %,p=0.87). The 2 –year overall survival was 71.6% in the TBI group and 46.2% in the chemotherapy group (p=0.11) but the difference was not significant. However, TBI-based regimen was significantly associated with a better 2-year event-free survival compared to chemotherapy-based regimen (72% versus 43%,p=0.03) Summary/Conclusion: Our findings support the use of TBI -based regimen in pediatric ASCT for ALL because it seems offering better outcomes compared to chemotherapy- based regimen. Keywords: Conditioning, Chemotherapy, Allo-SCT, Allogeneic hematopoietic stem cell transplant
PB1845: A MULTIOMIC, SINGLE-CELL MEASURABLE RESIDUAL DISEASE (SCMRD) ASSAY FOR PHASING DNA MUTATIONS AND SURFACE IMMUNOPHENOTYPES
Authors: Charlie Murphy, Kathryn Thompson, Lubna Nousheen, Aaron Llanso, Todd Druley, Adam Sciambi
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: The small population of cancerous cells that remain following treatment, known as measurable residual disease (MRD), is a strong predictor of relapse in acute myeloid leukemia (AML). Often, these refractory cells have gained additional resistance mutations or changed their surface immunophenotypes in ways that preclude detection or discrimination from preleukemic clones by current gold standard flow cytometry or bulk NGS assays. For this reason, a multi-omic single cell MRD assay could offer a more comprehensive indicator of relapse and the potential for faster response. Aims: Here, we present a new single-cell MRD (scMRD) assay with a 0.01% limit of detection, while also giving single cell clonal architecture and immunophenotyping to not only identify residual leukemia cells, but also identify putative DNA or protein targets for salvage therapy. Methods: The assay enables rare-cell detection on a standard Mission Bio Tapestri run by adding: (i) an upfront bead-based protocol to enrich for blast cells, (ii) a DNA and protein panel specifically designed for AML MRD diagnosis and treatment in alignment with both ICC and ELN guidelines, and (iii) a new automated analysis pipeline to evaluate single cell multiomics output. In addition, the multiplexing of up to three patient samples combined in one run via germline identification further reduces per sample costs and increases throughput. Results: Through the use of Mission Bio’s technology for detecting DNA variants in single-cells, this pipeline leverages variant-specific error modeling and single-cell co-occurrence to sensitively detect de novo variants, reducing false positive rates to achieve an LOD that meets and exceeds the recommended 0.1% cutoff for MRD-positivity by flow cytometry. It furthermore reconstructs the phylogenetic tree of the detected MRD cells, presents their surface protein signature and arm-level copy number changes. To demonstrate these features on MRD down to 0.01%, we present data from samples constructed by titrating diseased cells into healthy bone marrow cells before processing them with the scMRD assay. Summary/Conclusion: Combining high sensitivity with multi-omics, this assay offers a potential scalable solution for comprehensive AML MRD detection and guiding therapeutic decision-making.Keywords: Acute myeloid leukemia, Measurable residual disease, Immunophenotype, Somatic mutation
PB1759: RETAINED FUNCTIONAL NORMAL AND/OR PRE-LEUKEMIC HSCS IN THE BONE MARROW ARE ASSOCIATED TO GOOD PROGNOSIS IN DNMT3AMUTNPM1MUT AML PATIENTS
Authors: Elisa Donato, Nadia Correia, Carolin Andresen, Darja Karpova, Roberto Würth, Corinna Klein, Markus Sohn, Adriana Przybylla, Petra Zeisberger, Kathrin Rothfelder, Helmut Salih, Halvard Bonig, Sebastian Stasik, Christoph Röllig, Anna Dolnik, Lars Bullinger, Frank Buchholz, Christian Thiede, Daniel Hübschmann, Andreas Trumpp
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute Myeloid Leukemia (AML) is a highly aggressive adult leukemia with a high incidence of relapse and mortality. AML hijacked the hierarchical organization of normal hematopoiesis with Leukemia Stem Cells (LSCs) at the top of the differentiation tree and differentiated and highly proliferating myeloid blast at the bottom. Similar to normal hematopoietic stem cells (HSCs), LSCs have been originally identified as CD34+CD38- cells. However, this strategy to isolate LSCs is particularly challenging in NPM1 mutated AMLs, since expression of CD34 on leukemic cells is low or absent altogether. Aims: In this study, we aimed to establish a novel sorting strategy to isolate LSCs independently of CD34 surface marker in both CD34positive and CD34negative AMLs. Methods: Using a genetically highly homogeneous cohort of 46 AML patients carrying DNMT3A and NPM1 mutations, we established a novel isolation strategy to enrich for LSCs even in CD34negative AMLs by additionally including a positive selection for GPR56 and a negative selection for mature markers such as NKG2DLigandss. Results: By combining functional in vivo data, mutational analyses on xenografts and transcriptomic data, we found that CD34+GPR56+NKG2DL- subpopulations can contain along with LSCs also normal and/or pre-leukemic (HSCs). In contrast, no such residual normal or pre-leukemic HSCs were detected in CD34-GPR56+NKG2DL- subpopulations. Finally, we show that naïve AML patients who retain a relevant reserve of normal and/or preleukemic HSCs, able to reconstitute immunocompromised mice at time of diagnosis, have significant longer relapse-free and overall survival compared to patients without engrafting HSCs. Summary/Conclusion: These data suggest that the presence of normal and/or preleukemic HSCs with multilineage engrafting potential in the bone marrow of naïve patients is associated with good response to standard chemotherapy, providing a basis for the development of novel predictive biomarkers for standard chemotherapy regime. Keywords: DNMT3A, AML, Leukemic stem cell, Stem cell marker
P1464: CLINICAL COMPLICATIONS AMONG PATIENTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA IN GERMANY
Authors: Chuka Udeze, Colin Kunzweiler, Nanxin LI, Jessica Baldwin, Petra Tuzin, Sebastian Dietmar Barth, Céline Vetter, Silvia Dombrowski, Elena Georgiadou-Schmidt, Roland Meisel
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: β-thalassemia is a rare genetic disorder wherein patients have reduced or absent β-globin production, resulting in chronic anemia, iron overload, and other serious complications that can lead to early mortality. Patients with transfusion-dependent β-thalassemia (TDT) require lifelong supportive care, including regular red blood cell transfusions (RBCTs) and iron chelation therapies for survival. Aims: To describe clinical complications in patients with TDT in Germany. Methods: This longitudinal, retrospective cohort study utilized statutory health insurance records (Betriebskrankenkasse data source) in Germany to identify patients with a diagnosis for β-thalassemia between January 1, 2010, and December 31, 2018 (eligibility period). Eligible patients with TDT had ≥8 RBCTs in any 1-year period during the eligibility period and ≥1 year of follow-up after the first qualifying RBCT claim (i.e., index date, defined as the first RBCT of the ≥8 RBCTs during the eligibility period). Patients with hereditary persistence of fetal hemoglobin, sickle cell disease, or hematopoietic stem cell transplant in their medical records at any time were excluded. Patients were followed from index until the earliest of death, deregistration due to patient leaving the data source, or end of study period (December 31, 2019). Demographics were assessed at index. Acute and chronic complications (proportion of total population) were summarized descriptively during follow-up. Results: In total, 68 patients with TDT were included. Their mean age at index was 50.6 (standard deviation [SD]=26.0) years, and 30 (44.1%) were female. Average length of follow-up was 5.0 years. Patients with TDT averaged 16.4 (SD=11.2) RBCTs per-patient-per-year during follow-up. The most common acute complications were (>20% prevalence) cardiovascular complications (55.9%) and infections (25.0%). The most common cardiovascular complications were arrythmia (47.1%), heart failure (44.1%), and atrial fibrillation (26.5%). The most common chronic complications (>20% prevalence) were endocrine complications/bone disorders (69.1%); mental illness (depression or anxiety [36.8%]); urinary tract complications (36.8%); iron overload/hemochromatosis (33.8%); renal complications (32.4%); malignancies (30.9%); liver complications (25.0%); splenomegaly (23.5%); cardiovascular complications (22.1%); and myelodysplastic syndrome (22.1%). Diabetes (33.8%) and osteoporosis (30.9%) were the most common chronic endocrine complications/bone disorders. Summary/Conclusion: Despite the best available care, patients with TDT experience substantial burden due to clinical complications associated with the disease, highlighting the need for innovative therapies in this space. Keywords: beta thalassemia, Hemoglobinopathy, Complications
PB2076: GUIZHI FULING CAPSULE REGULATES AUTOPHAGY TO INTERFERE WITH BORTEZOMIB-INDUCED PERIPHERAL NEUROPATHY
Authors: Jiaqi Fu, Xing Cui
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Bortezomib is one of the frontline chemotherapeutic agents for multiple myeloma (MM) and has shown excellent efficacy1. However, bortezomib-induced peripheral neuropathy (BiPN) is the major dose-limiting toxicity and adversely affects the quality of life2. Accumulating evidence indicates that autophagy plays an important role in the occurrence and treatment of BiPN3. It has been reported that Guizhi Fuling capsule (GZFLC) possesses potent sedative, analgesic, antitumor, and neuroprotective properties without eliciting adverse effects4. Unfortunately, the neuroprotective effect of GZFL in BiPN remains unclear. Aims: To investigate the therapeutic effect and underlying mechanism of GZFLC on BIPN. Methods: The compounds and targets of GZFLC intervention in BIPN were determined by Q Exactive mass spectrometer and bioinformatics analysis. PC12-derived neuronal cell model and BIPN mice model (by intraperitoneal injection of bortezomib in C57BL/6J mice) were contrusted to evaluate the improvement of GZFLC on bortezomib-induced neurotoxicity. The alternation of autophagy level was detected by immunofluorescence staining, transmission electron microscopy (TEM), Western blotting (WB) and immunohistochemistry (IHC), respectively. Results: 34 components and 107 targets of GZFL for BiPN were obtained and were significantly enriched in autophagy-related pathways like the mTOR pathways (Figure A-C). GZFL significantly increased PC12 cell ability and the numbers of LC3 puncta and autophagic vesicles after bortezomib treatment. After combination treatment with the autophagy inhibitor, the effect of GZFL was reduced (Figure D-G). In vivo experiments showed that GZFL effectively improved the behavior of mice with BiPN and alleviated sciatic nerve injury (Figure H, I). TEM and IHC showed that GZFL remarkably enhanced autophagy, as indicated by the alternation of the autophagy-related protein levels in sciatic nerve tissue (Figure J, K).Summary/Conclusion: This work verified that GZFL could ameliorate peripheral neuropathy and protect the sciatic nerve from bortezomib-mediated damage, possibly by regulating the autophagy level. *Correspondence to: Xing Cui, M.D and Ph.D. Taishan Scholar, Professor. Email: [email protected]. Keywords: Multiple myeloma, Bortezomib
PB1777: THE AUTOMATED DATABASE-GUIDED STUDY OF THE PHENOTYPIC PROFILE IN CD34+ CD117+ HLADR+ PRECURSORS PROVIDES A SIMPLE AND RELIABLE STRATEGY FOR RAPID IDENTIFICATION OF CBF-MYH11+ ACUTE MYELOID LEUKEMIA.
Authors: Paula Piñero, Rocio Gonzalez, Vanesa Diaz, Javier López Marín, Cristina Gil, Carmen Botella, Pau Montesinos, Maria Amparo Sempere Talens, Fabian Tarin
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: CBF-MYH11+ acute myeloid leukemia (AML) is considered a good-prognosis AML in the context of cytarabine based intensive chemotherapy. The incorporation of gemtuzumab ozogamicin (GO) anti-CD33 in frontline therapy should be standard but requires a rapid diagnosis of this variant. Although the quickness of FISH and QPCR techniques have been improved, an early diagnostic orientation by morphology or flow cytometry can guide subsequent diagnostic confirmation strategies and facilitate the early incorporation of GO in the treatment of the disease. Aims: To develop a diagnostic strategy for the rapid detection of CBF-MYH11 AML, based on multiparametric flow cytometry (FCM) and automated techniques. Methods: Immunophenotypic study of bone marrow samples from patients with AML at diagnosis using the Euroflow SMD/LAM FCM standardized panel. Multiparametric comparative analysis of CD34+ leukemic myeloid precursors with databases of normal precursors for an automatic blast characterization. Study of BM samples by RT-PCR and FISH for a complete molecular diagnosis. Results: 1.The CD34+ precursors of patients with AML/CBF-MYH11 show a phenotypic profile differentiated from the other AMLs, characterized by an increased expression of CD13, CD15, CD64 and CD123 when comparing with databases of normal precursors (regardless of other markers) [Figure 1]. 2.It should be noted that these differences are subtle in many cases, making necessary to use automated tools and databases for their detection. 3.The overexpression of at least 3 of these 4 markers, together with the evidence of monocytic (>6%) and eosinophilic (>1%) maturation, allowed us to establish a highly reliable diagnostic score that shows a specificity close to 93% and a sensitivity greater than 99% (Odds ratio= 288.0; p<0.0001) [Figure 2] Summary/Conclusion: • The developed strategy allows a practically immediate diagnostic approximation of AML with CBF-MYH11 rearrangement, even in cases with ambiguous morphological characteristics. • This strategy has been incorporated into the routine of our laboratory, making possible the selection of cases with indication of an urgent molecular confirmation and the optimization of diagnostic workflows.Figure 1. Myeloid precursors immunophenotypeFigure 2: Maturation routes (blue: myeloid precursor/ green: monocytic differentiation/ magenta: granulocytic differentiation/ pink: eosinophilic differentiation Keywords: Flow cytometry, AML, Inv(16)
PB1714: DEXRAZOXANE IN HAEMATOLOGICAL PATIENTS: A META-ANALYSIS OF THE CARDIOPROTECTIVE EFFICACY, RISK OF SECONDARY MALIGNANCIES AND IMPACT IN SURVIVAL OUTCOMES
Authors: Mario Sousa Pimenta, Ana Meireles, Inês Ramos, Ângelo Martins, José M. Mariz
Journal: HemaSphere (2023)

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Anthracyclines’ exposure often leads to cardiotoxicity, influencing health-related quality of life, morbidity, and mortality. Therefore, combining a cardioprotective agent would be useful. The use of dexrazoxane (DRZ) as primary prophylaxis for cardiotoxicity in anthracycline-exposed patients is not consensual, considering the conflicting results regarding the risk of secondary neoplasms. This controversy justified the withdrawn of DRZ between 2011 and 2017. However, this drug was recently re-authorized by the European Medicines Agency for selected haematological patients. Aims: This meta-analysis aimed to pool DRZ effects in the setting of hematological neoplasms. We determined the cardioprotective effect, the risk of secondary neoplasms, as well as the difference of proportions in event-free survival (EFS) and overall survival (OS) rates in patients exposed and not exposed to DRZ. Methods: A systematic review and meta-analysis of clinical trials and case-control studies evaluating hematological patients exposed to anthracyclines and co-medicated with DRZ was performed according to PRISMA guidelines. For such, three online databases were searched up to January 2022. The odds ratio (OR), relative risk, and difference of proportions were calculated using the random-effects model; heterogeneity was assessed by the I2 method. Results: Overall, 420 studies were identified and 14 were included. DRZ was associated with significantly reduced overall cardiotoxicity (OR 0.34, 95% confidence interval [95% CI] 0.25-0.46, I2=0%), although at the expense of an increased risk of secondary neoplasms (OR 2.29, 95% CI 1.09-4.80, I2=0%). Exposure to DRZ had no impact on OS or EFS rates, even after adjustment for follow-up times. Studies quality was moderate, even though external validity was low. Summary/Conclusion: As far as the authors know, this is the first meta-analysis assessing the impact of DRZ specifically in haematological patients. We demonstrate its efficacy as a cardioprotective measure, but also the increased risk of secondary neoplasms. Further studies may analyze the patient- and disease-related characteristics that make individuals more prone to develop secondary neoplasms, herein allowing the selection of patients in whom the beneficial cardioprotective effect is associated with a safer profile. Keywords: Chemotherapy toxicity, Toxicity